Targeted Therapies for the Neurofibromatoses

Over the past several years, management of the tumors associated with the neurofibromatoses has been recognized to often require approaches that are distinct from their spontaneous counterparts. Focus has shifted to therapy aimed at minimizing symptoms given the risks of persistent, multiple tumors and new tumor growth. In this review, we will highlight the translation of preclinical data to therapeutic trials for patients with neurofibromatosis, particularly neurofibromatosis type 1 and neurofibromatosis type 2. Successful inhibition of MEK for patients with neurofibromatosis type 1 and progressive optic pathway gliomas or plexiform neurofibromas has been a significant advancement in patient care. Similar success for the malignant NF1 tumors, such as high-grade gliomas and malignant peripheral nerve sheath tumors, has not yet been achieved; nor has significant progress been made for patients with either neurofibromatosis type 2 or schwannomatosis, although efforts are ongoing.

Primary meningeal melanoma masquerading as neurofibromatosis type 2: illustrative case

BACKGROUND Primary meningeal melanocytic neoplasms are exceedingly rare tumors, representing only 0.06% to 0.1% of all primary brain tumors and ranging in spectrum from benign localized tumors to highly aggressive malignant lesions. The diagnosis of these tumors is often challenging from clinical, radiological, and pathologic standpoints. Equally challenging is the distinction between primary meningeal melanocytic neoplasm and metastatic melanoma. OBSERVATIONS The authors reported the case of a 41-year-old man with imaging findings diagnostic of neurofibromatosis type 2: bilateral internal auditory canal lesions (most consistent with bilateral vestibular schwannomas), two dura-based lesions presumed to be meningiomas, multiple spinal lesions consistent with peripheral nerve sheath tumors, and one intramedullary spinal lesion consistent with an ependymoma. Biopsy of these lesions revealed melanocytic neoplasms with mild to moderate atypia and a mildly elevated proliferation index, which made the distinction between benign and malignant challenging. In addition, the disseminated nature of these tumors made it difficult to determinate whether they arose from the meninges or represented metastases from an occult primary melanoma. LESSONS This case illustrated the challenges presented by the diagnosis of meningeal melanocytic neoplasms and highlighted the importance of integrating the clinical and radiographic findings with histologic appearance and molecular studies.

Neurocutaneous Disorders

Neurocutaneous disorders, formerly called phakomatoses, are characterized by cutaneous and neurologic findings. Many are genetic, but some are sporadic. Often these disorders affect other organ systems as well and require lifetime surveillance for complications. Neurofibromatosis type 1 is the most common neurocutaneous disorder. With a prevalence of approximately 1 in 3,000 persons, it is more than 10 times more common than neurofibromatosis type 2.

Clinical and molecular genetic features of neurofibromatosis type

Нейрофиброматоз 2 типа - редкое генетическое заболевание, этиологическим фактором развития которого являются мутации в гене-онкосупрессоре NF2, кодирующем белок мерлин. В обзоре подробно описаны структура, функции и посттрансляционные модификации мерлина, освещены клинические особенности нейрофиброматоза 2 типа, известные клинико-генетические корреляции, а также представлена информация о сайтах связывания мерлина и о функциональном вкладе расположенных в них мутаций, что закладывает базис персонализированной терапии нейрофиброматоза 2 типа. Neurofibromatosis type 2 is a rare genetic disorder caused by pathogenic mutations in the NF2 tumor suppressor gene which encodes a protein called merlin. This review describes the structure, functions, and post-translational modifications of merlin, highlights clinical features and known genotype-phenotype correlations of neurofibromatosis type 2, and provides information on the merlin binding sites and the functional contribution of mutations they harbor, which lays the basis for personalized therapy for neurofibromatosis type 2.